Thiamine deficiency (TD), a frequent complication of alcoholism or other disorders that interfere with normal ingestion of food, may result in brain damage. In chronic alcoholics, neurobehavioral deficits related to TD) has been shown to recover during abstinence with adequate nutrition. However, the mechanism(s) whereby thiamine treatment facilitates recovery of brain functions during detoxification and continued abstinence are not fully understood. In pyrithiamine-induced TD, using proton magnetic resonance spectroscopy, which allows non-invasive in vivo measurement of brain metabolites within anatomically determined volumes of interest, we have demonstrated a decrease in rat brain of MR-visible choline (Cho)- containing compounds relative to the neuronal marker, N-acetylaspartate (NAA). Cho/NAA increased in a dose-dependent fashion after thiamine hydrochloride treatment without change in relaxation time of Cho or NAA. In normal rats, for the first time, we found a measurable and reproducible dose-dependent increase in Cho peak by using in vivo localized MRS after administration of the acetylcholinesterase inhibitor, physostigmine. We are proposing to study whether recovery from pyrithiamine-induced TD in the rat provides a useful model for studying improvements of brain functioning as a result of recovery from malnutrition. First, we will characterize the Cho-containing compound(s) which change in brain extracts during pyrithiamine-induced TD and its reversal; determine the influence of concomitantly administered ethanol and choline on these compound(s). Second, we will investigate the dose- dependence of treatment with physostigmine, thiamine, and other drugs augmenting muscarinic cholinergic neurotransmission. Third, we will compare recovery of TD treated with either the optimal dose of thiamine hydrochloride, or the combination of this thiamine dose with a drug found to reverse the MRS changes of TD. These studies will further understanding of the pathophysiology of alcohol-induced brain damage and its prevention and treatment, specifically the rational dosing of thiamine and combined use with neuroprotective agents.